Heart failure affects over 5 million Americans and is the leading cause for hospitalization in the elderly. The renin-angiotensin-aldosterone system (RAAS) plays a central role in heart failure development and progression. Angiotensin converting enzyme (ACE) inhibitors are cornerstone therapy to suppress the RAAS; however, aldosterone levels rise in a subset of patients despite continued ACE inhibitor treatment. This phenomenon, known as aldosterone escape, may have important consequences given the deleterious effects of aldosterone on fluid volume and cardiac remodeling. There are limited data on whether genes for proteins that regulate aldosterone secretion influence the risk for aldosterone escape. The focus of this proposal is to determine whether the genes for ACE, aldosterone synthase (CYP11B2), atrial natriuretic peptide (NPPA), and p- glycoprotein (ABCB1) contribute to aldosterone escape during ACE inhibitor therapy in heart failure. The long-term goal of this line of investigation is to determine whether genotype is predictive of response to aldosterone antagonists in heart failure. This study will test the hypothesis that the ACE, CYP11B2, NPPA, and/or ABCB1 genes are associated with aldosterone escape in heart failure. Our specific aims are (1) to determine whether the ACE, CYP11B2, NPPA, and/or ABCB1 genes are associated with aldosterone escape in heart failure by comparing ACE I/D, CYP11B2 T-344C, NPPA C-664G and T2238C, and ABCB1 C3435T genotype frequencies between heart failure patients with a circulating aldosterone level >150 pg/ml despite ACE inhibitor treatment and those with a lower level; and (2) to examine the mechanism underlying genetic associations with aldosterone escape by estimating the correlation between circulating aldosterone and both angiotensin II and atrial natriuretic peptide concentrations in ACE inhibitor-treated heart failure patients. The proposed study is important because insight into genetic contributions to aldosterone escape could ultimately lead to the ability to predict which patients are at risk for aldosterone-mediated disease progression despite standard therapy, in whom the additional therapy to antagonize aldosterone might be particularly beneficial. [unreadable] PUBLIC HEALTH RELEVANCE: Heart failure is the most common cause for hospitalization in the elderly. Aldosterone is a hormone that promotes heart failure development and progression. This study aims to determine whether a person's genetic makeup affects his or her risk for elevated aldosterone levels despite standard therapy in heart failure. [unreadable] [unreadable] [unreadable]